The immune system is seriously impaired under various clinical situations and in older people. The long-term goal of our research is to define molecular interactions that are significant in the reconstitution of a functional immune system in adult mouse. T cell development in the thymus is a direct consequence of stage specific signal transduction and gene expression, resulting from reciprocal cell-cell interactions and locally produced cytokines and hormones. Cues from stromal cells modulate an exquisite balance of proliferation, quiescence, cell-death and cell-fate decisions in developing thymocytes. In turn, thymocytes modulate the maturation of thymic epithelial cells. Similarly, interactions between stromal cells and their products regulate T cell activation during immune response and inflammation. Recently, we have analyzed signals mediated by p38 MAP kinase, NF-kB and c-myc in the survival and differentiation of T cells in the thymus. Current major projects are focused on dissecting the mechanism by which the Wnt-beta-catenin signaling pathway interacts with signals from the pre T cell receptor (TCR) and TCR as well as Notch 1 to modulate T cell development, thymic aging and T cell function. Wnt-b-Catenin Pathway in the Development and Function of Immune Cells Because TCF-1 and LEF-1 have been shown to be critical for T cell maturation, we hypothesized that Wnt beta-catenin-TCF signaling pathway may be important in the thymus. We have determined that Wnt-1, -3A, -4 and -5A were expressed in thymocytes and using Wnt-1 Wnt-4 double deficient mice showed that Wnt-1 and Wnt-4 modulate thymic cellularity but not thymocyte differentiation. The role of beta-catenin, a central effecter of the Wnt-TCF-1 signaling pathway, in the regulation of T cell development was studied using genetically manipulated mice. In mice bearing T cell-specific deletion of beta-catenin, impaired signals through the pre-T cell receptor (TCR) and TCR undermined maturation and expansion of thymocytes resulting in significantly decreased splenic T cells. Lck-promoter driven transgenic expression of beta-catenin enhanced T cell maturation resulting in significantly increased mature thymocytes. Mechanistic studies suggest that positive selection was enhanced in the presence of ectopically expressed beta-catenin. Cat-Tg mice also exhibited enhanced thymic aging and involution. In summary, these data suggest that Wnt-beta-catenin-TCF-1 signaling pathway plays a role in normal T cell maturation at several stages of maturation. We are currently studying the molecular mechanisms underlying these observations and are studying the role of this pathway in T cell function and memory. We are also studying mice bearing tissue-specific beta-catenin deficiency in B cells and macrophages. The unifying theme of research in my lab is to explore how stage-specific gene-expression resulting from cell-cell interactions between thymic epithelial cells and thymocytes that modulate cell-survival, cell-death and differentiation in the thymus. Similarly, how signals from cell-cell interactions between antigen presenting cells and T cells modulate immune response in the peripheral immune system.